Submitted by Heitor Rapela Medeiros (heitor.rapela@ufpe.br) on 2015-03-06T12:37:03Z No. of bitstreams: 2 Dissertacao_Final_13_08-14_Fabio_queiroga.pdf: 1835518 bytes, checksum: 4868aed1cb91d21043f2bb5266455b63 (MD5) license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) / Made available in DSpace on 2015-03-06T12:37:03Z (GMT). No. of bitstreams: 2 Dissertacao_Final_13_08-14_Fabio_queiroga.pdf: 1835518 bytes, checksum: 4868aed1cb91d21043f2bb5266455b63 (MD5) license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Previous issue date: 2012-03-27 / A tuberculose (TB) em associação à infecção pelo HIV tem apresentações clínicas diferentes do habitual. Isso também acontece com imagens radiológicas que correspondem às lesões pulmonares atípicas em relação ao encontrado em indivíduos soronegativos com TB pulmonar. Este estudo teve, como objeto de investigação, indivíduos infectados pelo HIV que iniciaram tratamento para tuberculose pulmonar em um serviço de referência para HIV/AIDS, em Pernambuco (Hospital Correia Picanço), no período de 2007 a 2010. O principal objetivo foi verificar a associação entre a presença e o tipo de lesão pulmonar na radiografia de tórax, bem como os níveis de linfócitos CD4. Trata-se de um estudo observacional do tipo corte seccional com um componente analítico. Inicialmente, foram incluídos no estudo 182 pacientes que iniciaram tratamento para tuberculose, dos quais 64 foram excluídos da análise. A contagem mediana de células T CD4 dos pacientes analisados foi de 147,5 células/mm3. Entre os pacientes com CD4<200 células/mm3, as apresentações radiológicas mais encontradas foram: consolidação segmentar ou lobar, infiltrado difuso, infiltrado focal, derrame pleural, infiltrado miliar e linfonodomegalia. Não houve ocorrência de cavidades simples nos pacientes com CD4 abaixo de 200 células/mm3. Não se encontrou associação estatística significativa de nenhum acometimento pulmonar com nível de CD4, mesmo após o ajuste realizado. Os resultados sugerem que nenhuma alteração radiológica está associada aos níveis de linfócitos CD4 na população de indivíduos coinfectados pelo TB/HIV.

Circulating monocytes have the capacity to mature into either macrophages or dendritic cells in tissue, both of which play important roles in the induction and effector phase of immune response. In TB, the macrophages are the central player in the host-bacteria interaction as the main mycobacterial reservoir. In HIV disease, monocyte lineage cells are one of the two main cell types (along with CD4+ T-cells) in sustaining intracellular HIV infection. Monocytes are heterogeneous population with three functionally distinct subsets namely classical, intermediate and non-classical monocytes. The three subsets exist in a continuum, and have a certain plasticity or flexibility to develop into multiple roles depending on the local and tissue environment. In the current study we sought to evaluate the frequencies of these three subsets in participants with TB, HIV and TB/HIV co-infection. While previous studies had shown that the intermediate and non-classical monocyte subsets were elevated relative to classical monocytes, very little had been done in these disease groups regarding more comprehensive characterization of these subsets. In particular, we wished to quantitate the expression of multiple sets of cell surface and intracellular molecules of high relevance using multi-parameter flow cytometry from a functional point of view. In publication I, we evaluated Toll-like receptors (TLRs) expression in each of the study cohorts. TLRs are vital pattern recognition receptors by monocyte lineage cells and signal the induction of crucial functions. We focused on three such TLRs (TLR2, TLR4 and TLR9) which have been shown to be involved in many monocyte lineage cell interactions with mycobacterial and HIV infections. We observed enhanced expression of TLR2 and TLR4, but not TLR9 in TB and HIV. TLR4 was particularly high in patients with TB, but also in HIV. We observed comparable increase of TLR4 irrespective of monocyte subset. However, TLR2 expression exhibited a different pattern. Levels among the most prominent classical monocyte subsets were identical in all four cohorts, healthy controls (HC), HIV, TB, and TB/HIV co-infection. In contrast, TLR2 expression was significantly elevated in both participants with HIV and TB, but not with participants with TB/HIV co-infection in the intermediate monocyte subset. We also observed correlations between TLRs and plasma cytokines that were disease and TLR specific. In publication II, we observed elevated chemokine receptors (CRs) expression which above healthy controls and exhibit a pattern of disease preference. Thus, CCR2 and CX3CR1 were the highest in participants with TB, followed by HIV and TB/HIV co-infection, whereas CCR4 and CCR5 were highest in participants with HIV, and less elevated in TB. CCR2 and CX3CR1 are critical for migration of monocytes to sites of TB infection, as determined by murine models. CCR4 and especially CCR5 have been implicated in migration of cells to distant organs but more as co-receptors for HIV infection. Thus, the observed pattern of CRs expression in these monocytes in different disease states would predict greater availability of these cells or their receptors for interaction with either TB or HIV organisms. From the perspective of the pathogen this would lead to enhanced “substrate”, whereas from the perspective of the host, this could lead to greater immune potential. As a final point, we also observed that the pattern of disease association of CRs was independent of the monocyte subset. In publication III, we explored the expression of Programmed cell death-ligand 1 (PDL1) on the three monocyte subsets. Like many of the other molecules we have addressed in this thesis, PDL1 expression was enhanced in participants with HIV, TB, and TB/HIV co-infection. Among participants with HIV, PDL1 was correlated with HIV-1 viral load. The enhanced expression was apparent in all three subsets, but it was particularly prominent in the intermediate monocyte subset. Moreover, PDL1 expression was the highest in participants with TB/HIV co-infection. The implications behind these observations is that the subset thought to have the greatest potential for T cell antigen presentation had the highest levels of the T cell down-regulatory PDL1 molecule in the cohort of patients particularly participants with TB/HIV co-infection. Participants with TB/HIV co-infection have the greatest potential to be immuno-compromised and as a result the very need for enhanced not depressed APCs function. In addition, we also observed the PDL1 levels were correlated with multiple plasma, mostly pro-inflammatory,cytokines. We analyzed cytokine mRNA levels of total monocytes to address the source of the cytokines but mRNA levels did correlate with neither plasma cytokine nor PDL1 levels. Considering all the phenotype analysis in each of the three studies together we could see two patterns emerging. In one scenario,surface molecules expression patterns were disease specific but independent of monocyte subset expression. In other words, whatever the underlying mechanism(s) involved in their regulation, those mechanisms apparently acted similarly in all three subsets. In another scenario, expression of surface molecules showed disease specific patterns, but molecules were particularly enhanced in the intermediate monocyte subsets. These findings imply that there exist mechanisms to modulate surface phenotypes and functions that are unique to a given subset. In conclusion, we have comprehensively defined the density of multiple molecules expressed by different subsets of monocytes and explored their differences in participants with TB, HIV and TB/HIV co-infection, as well as their correlations with microbial indices and plasma cytokines. Many molecules levels were elevated to some extent in all disease cohorts, but we observed patterns of expression which were particularly elevated in TB (CCR2, CX3CR1, and TLR2), those in HIV (CCR4, CCR5) and those on both (TLR4, PDL1). Molecule-disease associations were either independent of monocyte subset, or most readily revealed in a single monocyte subset. TB/HIV co-infection did not follow a consistent pattern in association with monocytes markers, in some cases more resembling TB, in others HIV, in others neither. Finally, to proof one possible mechanism of association between disease and monocyte phenotype, we explored correlations between monocyte markers and plasma cytokines. We observed significant positive and negative associations, frequently unique to a single monocyte subset or disease cohort, such as TB/HIV co-infected cohort. Collectively, the results imply that there are likely multiple mechanisms involved at many levels regulating the phenotype and function of monocytes, and these differ in different disease states.:Abbreviations ............................................................................................................ 3 Abstract ..................................................................................................................... 4 1. Introduction ........................................................................................................... 6 1.1 Epidemiology of Tuberculosis and Human Immunodeficiency virus ................... 6 1.2 The immunological response to TB and HIV ....................................................... 7 1.2.1 Innate immunity of TB ...................................................................................... 7 1.2.2 Innate immunity of HIV .................................................................................... 11 1.2.3 Immune checkpoint regulation in TB and HIV.................................................. 13 1.3 The role of monocytes in TB, HIV and TB/HIV ................................................... 14 1.3.1 Monocytes ....................................................................................................... 14 1.3.2 Abnormalities of monocytes in TB ................................................................... 15 1.3.3 Abnormalities of monocytes in HIV ................................................................. 16 1.3.4 Abnormalities on monocytes in TB/HIV co-infection ....................................... 17 1.4 The rationale for the thesis ................................................................................ 17 2. Objectives ............................................................................................................ 19 3. Publications .......................................................................................................... 20 4. Summary .............................................................................................................. 65 References ............................................................................................................... 69 Annex I: Author contribution ..................................................................................... 76 Annex II: Declaration of independent writing of the work ......................................... 77 Annex III: Curriculum Vitea ....................................................................................... 78 Annex V: Acknowledgment........................................................................................ 82 Annex VI ................................................................................................................... 84

Syndrome inflammatoire lié à la reconstitution immunitaire chez le patient coinfecté par le VIH et la tuberculose est une complication du traitement par des antirétroviraux, appelé TB-IRIS. Ce syndrome est souvent rencontré dans les pays en voie de développement. Son diagnostic se pose essentiellement sur la présentation clinique et nécessiter de se différentier des autres pathologies. Son évolution est souvent favorable ou sous corticoïde mais certaine forme est sévère et/ou mortelle. L'étude de leur mécanisme permettra d'identifier de marqueur prédictif, applicable à leur diagnostic précoce et à l'amélioration de leur prise en charge. Alors, nous avons proposés d'étudier le rôle de cellule NK et le rôle de lymphocyte T dans l'essai clinique de CAMELIA au Cambodge. Le résultat a montré l'élévation de la capacité de dégranulation de cellule NK est associé à la survenu de TB-IRIS et il peut être un marqueur prédictif. De plus, l'hyperactivation de cellule T effectrice et la diminution de cellule T régulatrice sont aussi observées. Le rôle de cellule T régulatrice n'est pas encore préciser. Le mécanisme régulateur de ce phénomène doit être ultérieurement exploré. / Inflammatory syndrome associated with immune reconstitution in patients coinfected with HIV and TB is one complication of antiretroviral treatment, called TB-IRIS. This syndrome more often encountered in developing countries. Diagnosis of this syndrome is mainly based of clinical presentation and needs to differentiate from other diseases. Their evolution is usually favorable or under corticosteroids, but some cases are severe and / or fatal. The study of their mechanism could lead to identify predictive markers, applicable to their early diagnosis and improved their management. Thus, we proposed to study the role of NK cell and T cell in the CAMELIA clinical trials which have conducted in Cambodia. The result showed that higher increase of NK cell degranulation capacity was associated with the occurrence of TB-IRIS and it could be a predictive marker. Furthermore, the hyperactivation of effector T cell and decrease of regulatory T cell were also observed. The implication of the regulatory T cell in this syndrome was not clear yet. The regulatory mechanism of this phenomenon should be further explored

Magister Public Health - MPH / BACKGROUND: Namibia has generalised Human Immunodeficiency Virus (HIV) and tuberculosis (TB) epidemics. In response to the TB/HIV co-epidemics in Namibia, the Ministry of Health and Social Services approved a policy of TB/HIV collaborative activities at national level and the integration of TB/HIV services at the point of service delivery. The present study explored barriers and facilitators of integration of TB and HIV service delivery in Tsandi District Hospital, which lies in rural northern Namibia. It focused on understanding the perspectives of healthcare workers and service users on integration of TB and HIV services at the health facility. AIMS & OBJECTIVES: The study aimed to describe the barriers, facilitators, and opportunities of integrated TB/HIV service delivery in Tsandi District Hospital. The specific objectives were: to describe the staffing and support systems in place for the integration of TB/HIV care; to describe the perceptions and experiences of integrated TB/HIV care by the health care workers, management and co-infected clients; and to describe the factors that facilitate or hinder the integration of TB/HIV services in the district from the point of view of district hospital managers, health care workers and co-infected clients. METHODS: The study used a descriptive qualitative study design with semistructured key-informant interviews conducted with five healthcare managers and senior clinicians and focus group discussions with 14 healthcare workers and five TB/HIV co-infected patients, supplemented by non-participant observation in Tsandi district hospital over two weeks between May – June 2011. Sessions were audiorecorded, transcribed, and thematically analysed. RESULTS: Several factors influenced whether and to what degree Tsandi district hospital was able to achieve integration of TB and HIV services. These are: (1) model of care and nature of referral links; (2) the availability and use of human resources and workspace; (3) the system of rotating staff among departments in the hospital; (4) the supply and mode of providing medicines to patients; (5) information systems, recording and reporting arrangements; (6) and the amount of follow-up and supervision of the integrated services. The main suggested barrier factors are: (1) poor communication and weak referrals links between services; (2) inadequate infrastructure to encourage and deliver TB and HIV care; (3) staff shortages and high workload; (4) lack of training and skills among healthcare workers; (5) financial constraints and other socioeconomic challenges; and (6) fragmented recording and reporting systems with limited data use to improve service delivery. The four main facilitating factors are: (1) positive staff attitudes towards TB/HIV integration; (2) common pool of staff managing different programmes; (3) joint planning and review of TB and HIV activities at the ARV Committee; and (4) informal task sharing to alleviate healthcare worker shortages. CONCLUSIONS: This study recommends that the district build on the current facilitators of integration, while the inhibitors should be worked on in order to improve the delivery of TB/HIV services in the district. Simple and practical recommendations have been made to address the some of the barriers at district level. It is hoped that these will inform future planning and review of the current model of care by the District nagement Team.

Submitted by Pós Imunologia (ppgimicsufba@gmail.com) on 2017-02-14T16:02:01Z No. of bitstreams: 1 Tese ELISABETE LOPES CONCEIÇÃO.pdf: 1470553 bytes, checksum: a38beb6dfeaae41d703bf5282cabb0a3 (MD5) / Approved for entry into archive by Uillis de Assis Santos (uillis.assis@ufba.br) on 2017-06-20T20:34:44Z (GMT) No. of bitstreams: 1 Tese ELISABETE LOPES CONCEIÇÃO.pdf: 1470553 bytes, checksum: a38beb6dfeaae41d703bf5282cabb0a3 (MD5) / Made available in DSpace on 2017-06-20T20:34:44Z (GMT). No. of bitstreams: 1 Tese ELISABETE LOPES CONCEIÇÃO.pdf: 1470553 bytes, checksum: a38beb6dfeaae41d703bf5282cabb0a3 (MD5) / Capes / O Mycobacterium tuberculosis e o vírus da imunodeficiência humana (HIV) agem em sinergia prejudicando a resposta imune para eliminação de ambos os patógenos. Fatores genéticos dos hospedeiros podem ser determinantes para o risco de progressão da tuberculose (TB) e infecção pelo HIV. Algumas variações genéticas têm sido associadas a diferenças no potencial para indução de apoptose e a alterações na produção de citocinas, tais como os polimorfismos de base única (SNPs) TNF-308G>A, DDX39B -22 G>C e -348C>T. Outra característica que acompanha a evolução da infecção é o estresse oxidativo sistêmico e o aumento da peroxidação. A Heme oxigenase-1 (HO-1) é o principal agente anti-oxidante expresso no tecido pulmonar, uma enzima de resposta ao estresse que degrada moléculas heme para a liberação de íons ferro, monóxido de carbono (CO) e biliverdina (BV). O presente trabalho propôs investigar fatores genéticos e imunológicos relacionados à imunopatogênese da TB e co-infecção TB-HIV. Para a realização do trabalho foram realizados: 1) uma revisão sistemática da literatura sobre os polimorfismos genéticos envolvidos nas vias e morte e associados com TB, 2) um estudo observacional de corte transversal para determinar a frequência de polimorfismos em voluntários monoinfectados com TB latente ou ativa e coinfectados com TB-HIV. Para este último foram recrutados 109 pacientes com tuberculose pulmonar (PTB), 60 pacientes coinfectados com HIV (TB-HIV) e 74 indivíduos com infecção tuberculosa latente (LTBI), e 3) Uma coorte avaliando os níveis de HO-1 e MMP-1 em pacientes com TB. Na revisão sistemática os polimorfismos dos genes do TNF, TNFR, IL-1 e P2RX7 estavam associados com tuberculose. No estudo de corte transversal a frequência do genótipo TNF-308G foi maior para o grupo LTBI comparado com TB e TB-HIV. A produção de TNF foi maior 8 entre os pacientes com PTB portadores do genótipo TNF -308GG. Os níveis de IL- 1α e IL-1β também foram mais elevados entre os pacientes com PTB portadores dos genótipos DDX39B -22CC e DDX39B -348CC. Não houve relação entre a produção de citocinas e a extensão da doença. Na coorte, os pacientes com TB apresentaram uma dicotomia na resposta de HO-1 MMP-1 com dois fenótipos, HO-1hiMMP-1lo e MMP-1 HO-1loMMP-1hi. Nosso estudo sugere que polimorfismos envolvidos na via de morte podem estar associados com susceptibilidade para o desenvolvimento da tuberculose, contudo, a frequência dos alelos e genótipos para os polimorfismos estudados não diferiram na co-infecção pelo HIV. O mecanismo entre o estresse oxidativo e remodelamento do tecido pode ter aplicabilidade clínica nos estágios da progressão da TB. / Mycobacterium tuberculosis and human immunodeficiency virus (HIV) act synergistically damaging immune response to eliminate both pathogens. Genetic factors of the host can be decisive for the risk of progression of tuberculosis (TB) and HIV infection. Some genetic changes have been associated with differences in potential for induction of apoptosis and changes in cytokine production such as single nucleotide polymorphisms (SNPs) TNF-308G> A, DDX39B -22 G> C and -348C> T. Another feature that monitors the infection is systemic oxidative stress and increased peroxidation. The heme oxygenase-1 (HO-1) is the primary anti-oxidant expressed in lung tissue, a response of the enzyme to stress that degrades heme molecules to the release of iron ions, carbon monoxide (CO), and biliverdin (BV) . This study proposed to investigate genetic and immunological factors related to TB immunopathogenesis and co-infection TB-HIV. To carry out the work were performed: 1) a systematic review of the literature on genetic polymorphisms involved in the pathways and death associated with TB, 2) an observational cross-sectional study to determine the frequency of polymorphisms in volunteers monoinfected with latent TB or active and co-infected with TB-HIV. For the latter were recruited 109 patients with pulmonary TB (PTB), 60 patients co-infected with HIV (HIV-TB) and 74 individuals with latent tuberculosis infection (LTBI), and 3) a cohort evaluating the levels of HO-1 and MMP- 1 in patients with TB. In the systematic review of TNF polymorphisms of genes, TNFR, IL-1 and P2RX7 were associated with tuberculosis. In the cross-sectional study the frequency of TNF-308G genotype was higher for LTBI group compared with TB and TB-HIV. The production of TNF was higher among patients with PTB patients TNF -308GG genotype. IL-1α and IL-1β were also higher among patients 10 with genotypes of PTB patients DDX39B -22CC and DDX39B -348CC. No relation between the production of cytokines and the extent of disease. In cohort, patients with TB presented a dichotomy in HO-1 MMP-1 response with two phenotypes, HO- 1hiMMP-1lo HO-1 and MMP-1loMMP-1hi. Our study suggests that polymorphisms involved in the death pathway may be associated with susceptibility to the development of tuberculosis, however, the frequency of alleles and genotypes for the studied polymorphisms did not differ in co-infection with HIV. The mechanism of oxidative stress and remodeling of the tissue may have clinical applicability in the progression of TB staging.

Magister Public Health - MPH / BACKGROUND: Namibia has generalised Human Immunodeficiency Virus (HIV) and tuberculosis (TB) epidemics. In response to the TB/HIV co-epidemics in Namibia, the Ministry of Health and Social Services approved a policy of TB/HIV collaborative activities at national level and the integration of TB/HIV services at the point of service delivery. The present study explored barriers and facilitators of integration of TB and HIV service delivery in Tsandi District Hospital, which lies in rural northern Namibia. It focused on understanding the perspectives of healthcare workers and service users on integration of TB and HIV services at the health facility. AIMS & OBJECTIVES: The study aimed to describe the barriers, facilitators, and opportunities of integrated TB/HIV service delivery in Tsandi District Hospital. The specific objectives were: to describe the staffing and support systems in place for the integration of TB/HIV care; to describe the perceptions and experiences of integrated TB/HIV care by the health care workers, management and co-infected clients; and to describe the factors that facilitate or hinder the integration of TB/HIV services in the district from the point of view of district hospital managers, health care workers and co-infected clients. METHODS: The study used a descriptive qualitative study design with semi-structured key-informant interviews conducted with five healthcare managers and senior clinicians and focus group discussions with 14 healthcare workers and five TB/HIV co-infected patients, supplemented by non-participant observation in Tsandi district hospital over two weeks between May – June 2011. Sessions were audio-recorded, transcribed, and thematically analysed. RESULTS: Several factors influenced whether and to what degree Tsandi district hospital was able to achieve integration of TB and HIV services. These are: (1) model of care and nature of referral links; (2) the availability and use of human resources and workspace; (3) the system of rotating staff among departments in the hospital; (4) the supply and mode of providing medicines to patients; (5) information systems, recording and reporting arrangements; (6) and the amount of follow-up and supervision of the integrated services. The main suggested barrier factors are: (1) poor communication and weak referrals links between services; (2) inadequate infrastructure to encourage and deliver TB and HIV care; (3) staff shortages and high workload; (4) lack of training and skills among healthcare workers; (5) financial constraints and other socioeconomic challenges; and (6) fragmented recording and reporting systems with limited data use to improve service delivery. The four main facilitating factors are: (1) positive staff attitudes towards TB/HIV integration; (2) common pool of staff managing different programmes; (3) joint planning and review of TB and HIV activities at the ARV Committee; and (4) informal task sharing to alleviate healthcare worker shortages. CONCLUSIONS: This study recommends that the district build on the current facilitators of integration, while the inhibitors should be worked on in order to improve the delivery of TB/HIV services in the district. Simple and practical recommendations have been made to address the some of the barriers at district level. It is hoped that these will inform future planning and review of the current model of care by the District Management Team.

O estudo teve como objetivo analisar os determinantes sociais da saúde associados à mortalidade por TB e verificar as mortes precoces ocorridas por TB e TB/HIV e seus fatores associados, por meio de duas abordagens: uma de base ecológica e uma de base individual, utilizando análise espacial e de sobrevida. O estudo foi realizado na capital do Paraná, Curitiba; e, para análise espacial, foram consideradas as 148 unidades de desenvolvimento humano (UDH). A população de estudo foi composta dos casos de mortes por TB como causa básica (CID 15-19). Para análise de sobrevida, foram acrescidos os casos de mortes pela coinfecção TB/HIV (CID 20.0). Os dados foram obtidos do Sistema de Informação sobre Mortalidade (SIM) e do Sistema de Informações sobre Doenças de Notificação (SINAN) referentes ao período 2008 a 2015. As Unidades de Desenvolvimento Humano foram caracterizadas de acordo com a mortalidade por TB e com as variáveis dos determinantes sociais da saúde. Inicialmente os casos de óbitos por TB foram geocodificados e calculadas taxas de mortalidade bruta, taxa Bayesiana e investigados quanto à autocorrelação espacial e existência de aglomerados de risco por meio da técnica de varredura espacial e obtidos riscos relativos espaciais. Para correlacionar as áreas de risco espacial para mortalidade por TB foi utilizada a regressão logística, tendo como variável dependente área de risco: sim e não, e após avaliado com uso da curva ROC, também foi elaborado um mapa de sobreposição de áreas de risco dos determinantes sociais da saúde e correlacionados com aglomerados de risco para mortalidade. Por último, para investigar as mortes precoces por TB e TB/HIV e fatores associados foi utilizada a técnica de Kaplan-Meier e Regressão de Cox. Foram identificados 131 óbitos por TB, dos quais 126 (96,2%) foram geocodificados e 05 (4,8%) foram excluídos devido a endereços incompletos. Para a primeira fase, foram calculadas as taxas resultado em taxa média bruta de 1,07/100.000 habitantes. As mortes estiveram distribuídas de maneira difusa, porém, com maior concentração nas regiões periféricas e sul do município. Foi detectado um aglomerado espacial de risco na região sul para mortalidade por TB e para variáveis dos determinantes sociais da saúde, sendo onde as piores condições foram detectadas. O estudo confirmou a relação entre os determinantes sociais e as áreas de risco de mortes por TB quando relacionados com a Dimensão 1 extraída com (OR= 0,093; IC95% 0,34-0,25). O mapa de sobreposição dos aglomerados de risco relacionados com aglomerado para mortalidade por TB resultou em um OR= 5,98 (IC95%: 2,41-14,49) e curva ROC= 0,865; IC95%=0,796-0,934. Na segunda fase, ao analisar as mortes precoces por TB, foi encontrada uma mediana de dias sobrevividos de 22 dias, sendo que 88 (59,1%) dos pacientes morreram até 30 dias após o diagnóstico e 107 (72,5%) após 60 dias (mínimo: 1, máximo: 349, D.P: 68,8 e média: 50 dias). Dentre os 179 óbitos analisados, 105 (58,6%) óbitos tinham diagnóstico de TB (CID 15.0-19) e 74 (41,4%) óbitos a coinfecção TB/HIV (CID 20.0). A maioria dos casos ocorreu em pessoas do sexo masculino, 138 (77,1%), da raça/ cor branca predominante 120 (67%) e a média de idade foi de 47 anos (mínimo:20, máximo: 94, mediana: 44, DP: 14). Os resultados corroboram com a necessidade de melhorias múltiplas nas condições de vida da população, com enfoque nas regiões mais vulneráveis (áreas de aglomerados de risco espacial) identificadas e políticas específicas para prevenção do uso de álcool, diante da identificação deste fator associado às mortes precoces / The objective of the study was to analyze the social determinants of health associated with TB mortality and to verify the early deaths caused by TB and TB / HIV and their associated factors, through two approaches: one based on an ecological basis and an individual basis using analysis spatial and survival The study was carried out in the capital of Paraná, Curitiba; and for spatial analysis, the 148 human development units (UDH) were considered. The study population was composed of cases of TB deaths as the underlying cause (ICD 15-19). Survival analysis included cases of TB / HIV coinfection deaths (ICD 20.0). Data were obtained from the Mortality Information System (SIM) and the Notification Disease Information System (SINAN) for the period 2008 to 2015. The Human Development Units were characterized according to TB mortality and the variables determinants of health. Initially the cases of TB deaths were geocoded and gross mortality rates, Bayesian taxa were calculated and investigated for spatial autocorrelation and existence of clusters of risk by means of the spatial scanning technique and obtained relative spatial risks. In order to correlate spatial risk areas with mortality from TB, logistic regression was used as a risk variable: yes and no and after being evaluated using the ROC curve, a map of overlapping risk areas of social determinants correlated with clusters of risk for mortality. A total of 131 TB deaths were identified, 126 (96.2%) of which were geocoded and 05 (4%) of the deaths were TB and HIV and associated factors were Kaplan-Meier and Cox Regression. A total of 131 TB deaths were identified, of which 126 (96.2%) were geocoded and 05 (4.8%) were excluded due to incomplete addresses. For the first phase, the results were calculated at a gross average rate of 1.07 / 100,000 inhabitants. The deaths were distributed in a diffuse way, however, with greater concentration in the peripheral and southern regions of the municipality. It was detected a spatial cluster of risk in the southern region for mortality by TB and for variables of the social determinants of health and where the worst conditions were detected. The study confirmed the relationship between social determinants and risk areas for TB deaths when related to Dimension 1 extracted with (OR= 0,093; IC95% 0,34-0,25). The map of overlapping cluster-related risk clusters for TB mortality resulted in an OR= 5.95 IC95%=2.41-14.49 and ROC curve= 0.865 (CI95%= 0.796-0.934). In the second phase, when analyzing the early TB deaths, a median number of surviving days of 22 days was found, of which 88 (59.1%) died within 30 days after diagnosis and 107 (72.5%) after 60 days days (minimum: 1, maximum: 349, SD: 68.8 and average: 50 days). Among the 179 deaths analyzed, 105 (58.6%) deaths had a diagnosis of TB (ICD 15.0-19) and 74 (41.4%) had TB / HIV co-infection (ICD 20.0). The majority of the cases occurred in males, 138 (77.1%), the predominant white race (67%) and the mean age was 47 years (minimum: 20, maximum: 94, median: 44, DP: 14). The results corroborate the need for multiple improvements in the living conditions of the population, with a focus on the most vulnerable regions (areas of agglomerates of spatial risk) identified and specific policies to prevent alcohol use, in view of the identification of this factor associated with early deaths

Tuberculosis (TB) is the most common opportunistic infection in HIV-infected patients and the emergence of drug-resistant tuberculosis (DR-TB) is a growing problem in resource-limited settings (RLS). TB diagnosis in most RLS still depends on smear microscopy for acid-fast bacilli (AFB) while adequate infrastructure for testing drug sensitivity is unavailable. However, molecular diagnostics that detect Mycobacterium tuberculosis (Mtb) DNA and its genetic markers of drug resistance were recently developed. In this thesis I describe the use of a molecular diagnostic, Genotype MTBDRplus, for characterizing DR-TB and patterns of tuberculosis-like infection in two cities in south-west and north-central Nigeria. I found high rates of DR-TB in Nigerian HIV-infected individuals (9.3% for RIF or INH) with significantly different amounts by location (18.18% in south-west vs. 3.91% in north-central Nigeria, p=0.01). RIF resistance, indicative of MDR-TB, was found in 5.52% treatment-naïve patients, far exceeding the WHO predictions (0-4.3%). Furthermore, RIF resistance was genetically distinct, suggesting location-specific transmission of drug resistance (p=0.04). Genotype MTBDRplus correctly identified the drug-resistant samples compared to sequencing in 96.8% of cases. Mtb was confirmed in 56% of patients and was less likely to be found in patients on ART, while controlling for other relevant demographic characteristics (OR 0.29, P=0.02). Only abnormal respiratory findings on auscultation and the direct sputum smear grade greater than 3/100 were significant predictors of Mtb infection (OR 3.28, P=0.03; OR 6.40, p<0.01 respectively). Concentrated sputum smear was not significantly correlated with Mtb infection, except at the highest grades (>2+). Furthermore, in 49% of samples that were not confirmed for Mtb other actinomycetes were found: atypical Mycobacteria (ATM), Rhodococcus spp., Nocardia spp., Corynebacterium spp. I conclude that concentrated sputum AFB smears may misidentify bacteria as Mtb in a subset of HIV-infected patients. These individuals may have a different, even uncharacterized, actinomycete infection in the respiratory tract. Furthermore, total DR-TB in HIV-infection is high and transmission of DR-TB in HIV-infected patients in Nigeria is higher than estimated by the WHO. Molecular diagnostics are a rapid method for identifying Mtb and monitoring DR-TB, and can guide appropriate treatment decisions for respiratory infections in RLS with a high HIV burden.

Tuberculosis (TB) is an airborne infection. Though effective anti-TB drugs have been available for more than 50 years, over one-third of the world’s population is exposed to TB bacterium; deaths due to TB infection occur at high frequency every day worldwide. Today, drug-resistant TB, TB/HIV co-morbidity and poor health infrastructure are major challenges worldwide, particularly in less developed countries. The primary objective of the study was to assess the progress of TB control programs in twenty-two Eastern Mediterranean Region countries toward Millennium Development Goals (MDGs) including implementation of the Directly Observed Treatment, Short-course (DOTS). Also, the study was designed to explore TB/HIV co-morbidity and to assess some factors potentially associated with TB progress in the region. Secondary data, obtained from the World Health Organization, World Bank, and World Resource Institute on line databases were used. Paired samples t-test and bivariate correlation were conducted. Between 1990 and 2005, TB incidence had decreased 9%, TB prevalence had decreased 37% (statistically significant) and TB mortality had decreased 28%; nevertheless, MDG targets were not met. TB/HIV co-morbidity increased in the region especially in HIV-high burden countries. Though DOTS population coverage was increased to 94% in 2005, DOTS new smear-positive case detection rate was 61% (target 70%) and DOTS treatment success was 80% (target 85%). Thus, the 1991 Stop TB Partnership targets were not met. In spite of the progress of TB control programs in the EMR, MDGs and DOTs targets of 2005 were not obtained. Further efforts such as allocation of more resources, strengthening of TB surveillance systems, extension of drug-resistant TB and TB/HIV collaborative programs, and TB research are required to achieve MDGs by 2015 and to fully implement the new Stop TB Strategy in the region.

Made available in DSpace on 2014-06-11T19:27:21Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-03-14Bitstream added on 2014-06-13T20:16:36Z : No. of bitstreams: 1 pedro_hsp_me_sjrp.pdf: 1004378 bytes, checksum: d89276d95fd4738ef5918762497df5ea (MD5) / São José do Rio Preto (SJRP), localizada na região Noroeste do Estado de São Paulo, Sudeste do Brasil, é considerada Município prioritário pelo Programa Nacional de Controle da Tuberculose e da AIDS. O objetivo deste trabalho foi avaliar retrospectivamente pacientes infectados pelo HIV com pelo menos um isolamento de Mycobacterium sp., atendidos em unidades de saúde de referência de SJRP e região, bem como descrever seus aspectos clínicos e sócio–demográficos. Foram avaliados no período de janeiro de 2000 a dezembro de 2006, 198 indivíduos soropositivos para o HIV com culturas positivas no Instituto Adolfo Lutz de SJRP. Houve uma correlação positiva entre a tuberculose e o registro de detenção (p=0.021). O uso do tabaco reduziu o tempo de vida entre o diagnóstico e o óbito (p=0.05). Houve associação entre o isolamento de M. tuberculosis (MT) e os níveis de linfócitos TCD4+ bem como o achado difuso para RX de tórax (p=0.014 e 0.000, respectivamente). Aproximadamente 11% de todas as cepas de MT mostraram resistência a pelo menos uma droga, enquanto 3.1% foram multiresistentes. Micobactérias não tuberculosas (MNT) totalizaram 35.19% de todos os isolamentos e a maioria das espécies pertence ao complexo Mycobacterium avium (MAC; 22.3%), seguido por M. fortuitum (5.2%) e M.gordonae (3.1%). Conclui-se que a população HIV estudada tem alta prevalência de colonização por MNT. Em um país com extensão continental como o Brasil, o conhecimento das diferenças regionais na distribuição de MNT em populações infectadas pelo HIV pode contribuir para o controle e tratamento dessas infecções oportunistas. / São José do Rio Preto city (SJRP), Northwestern São Paulo State, Southeast Brazil, is considered “priority” by the National Programs of Tuberculosis and AIDS Control. Our purpose was to retrospectively evaluate Mycobacterium sp. isolated from HIV-infected patients attending the HIV/TB reference health care units from SJRP and region, as well as to describe their clinical and socio-demographic aspects. One hundred and ninetyeigth HIV-seropositive individuals provided 287 positives cultures from January 2000 to December 2006. There was a positive correlation between tuberculosis and prison record (p=0.021) and tobacco use reduced the mean lifetime from tuberculosis diagnosis to obit (p = 0.05). TCD4+ levels and a diffuse chest X-ray finding were associated to Mycobacterium tuberculosis (MT) isolation (p = 0.014 and 0.000, respectively). Approximately eleven percent of all MT strains showed resistance to at least one drug while 3.1% were multidrug resistant. Non-tuberculous mycobacteria (NTM) totalized 35.19% of all species and the most frequently isolated ones were Mycobacterium avium complex (MAC; 22.3%), M. fortuitum (5.2%) and M. gordonae (3.1%). We conclude that the HIV-infected population studied has a high prevalence of NTM colonization. In a wide country like Brazil, regional differences on NTM distribution in HIV-infected individuals must be further evaluated in order to improve control and treatment of these opportunistic infections.